1J3K

Quadruple mutant (N51I+C59R+S108N+I164L) Plasmodium falciparum dihydrofolate reductase-thymidylate synthase (PfDHFR-TS) complexed with WR99210, NADPH, and dUMP

Summary for 1J3K

• Entry DOI: 10.2210/pdb1j3k/pdb
• Related: 1J3I 1J3J
• Descriptor: Bifunctional dihydrofolate reductase-thymidylate synthase, 6,6-DIMETHYL-1-[3-(2,4,5-TRICHLOROPHENOXY)PROPOXY]-1,6-DIHYDRO-1,3,5-TRIAZINE-2,4-DIAMINE, NADPH DIHYDRO-NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE, ... (6 entities in total)
• Functional Keywords: bifunctional, oxidoreductase, transferase
• Biological source: Plasmodium falciparum (malaria parasite P. falciparum); More
• Total number of polymer chains: 4
• Total formula weight: 146749.09

Authors

Yuvaniyama, J.,Chitnumsub, P.,Kamchonwongpaisan, S.,Vanichtanankul, J.,Sirawaraporn, W.,Taylor, P.,Walkinshaw, M.,Yuthavong, Y. (deposition date: 2003-02-03, release date: 2003-05-06, Last modification date: 2023-12-27)

Primary citation

Yuvaniyama, J.,Chitnumsub, P.,Kamchonwongpaisan, S.,Vanichtanankul, J.,Sirawaraporn, W.,Taylor, P.,Walkinshaw, M.D.,Yuthavong, Y.
Insights into antifolate resistance from malarial DHFR-TS structures.
NAT.STRUCT.BIOL., 10:357-365, 2003

PubMed Abstract: Plasmodium falciparum dihydrofolate reductase-thymidylate synthase (PfDHFR-TS) is an important target of antimalarial drugs. The efficacy of this class of DHFR-inhibitor drugs is now compromised because of mutations that prevent drug binding yet retain enzyme activity. The crystal structures of PfDHFR-TS from the wild type (TM4/8.2) and the quadruple drug-resistant mutant (V1/S) strains, in complex with a potent inhibitor WR99210, as well as the resistant double mutant (K1 CB1) with the antimalarial pyrimethamine, reveal features for overcoming resistance. In contrast to pyrimethamine, the flexible side chain of WR99210 can adopt a conformation that fits well in the active site, thereby contributing to binding. The single-chain bifunctional PfDHFR-TS has a helical insert between the DHFR and TS domains that is involved in dimerization and domain organization. Moreover, positively charged grooves on the surface of the dimer suggest a function in channeling of substrate from TS to DHFR active sites. These features provide possible approaches for the design of new drugs to overcome antifolate resistance.

PubMed: 12704428
DOI: 10.1038/nsb921

Experimental method

X-RAY DIFFRACTION (2.1 Å)